Lessons From the Testosterone Trials

Abstract

The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk.

Figure 1.

Modified CONSORT (Consolidated Standards of Reporting Trials) diagram of participants in TTrials showing the flow of men from initial screening through enrollment, treatment, and completion of the trial. IPSS, International Prostate Symptom Score.

Figure 2.

Serum concentrations of testosterone, free testosterone, and estradiol at baseline and during 12 months of treatment with testosterone or placebo. The shaded areas represent the ranges of normal for young men. Values presented as median ± interquartile range. Adapted, with permission, from Snyder et al. (19).

Figure 3.

Effect of testosterone on sexual activity. Change from baseline in sexual activity, as assessed by the Psychosexual Daily Questionnaire, question 4, in (left) men taking testosterone or placebo and enrolled in the Sexual Function Trial and (right) all men enrolled in the TTrials. Data presented as means and 95% confidence intervals.

Figure 4.

Effect of testosterone on walking distance. Graphs showing percentage of (left) men taking testosterone or placebo and enrolled in the Physical Function Trial and (right) all men enrolled in TTrials whose distance walked in 6 minutes increased by ≥50 m greater than the baseline. Data presented as means and 95% confidence intervals.

Figure 5.

Effect of testosterone on vitality and fatigue. Graphs showing percentage of (left) men taking testosterone or placebo and enrolled in the Vitality Trial and (right) all men enrolled in TTrials whose score on the FACIT-fatigue scale increased by ≥4 points greater than baseline. Data presented as means and 95% confidence intervals.

Figure 6.

Effect of testosterone on anemia. Men (top) who were anemic at baseline for no known reason (unexplained) or (bottom) who had a known cause were treated with testosterone or placebo. (Left) The percentage of men who experienced an increase in hemoglobin of ≥1.0 g/dL. (Right) Absolute increases in hemoglobin. Data presented as means ± pointwise confidence intervals. Adapted, with permission, from Roy et al. (37).

Figure 7.

Change from baseline to 12 months in (top) vBMD and (bottom) estimated bone strength, as determined by QCT in trabecular, peripheral, or whole bone of the spine or hip in 211 men treated with testosterone or placebo. Data presented as mean ± standard deviation. Reproduced, with permission, from Snyder et al. (42).

Figure 8.

Change from baseline to 12 months in noncalcified coronary artery plaque volume, as determined by CTA, in 138 men treated with testosterone or placebo. Data presented as least square mean ± 95% confidence intervals.